Neuro Oncol. 2024 Dec 24:noae233. doi: 10.1093/neuonc/noae233. Online ahead of print.

NO ABSTRACT

PMID:39718993 | DOI:10.1093/neuonc/noae233

Nucleic Acids Res. 2024 Dec 24:gkae1265. doi: 10.1093/nar/gkae1265. Online ahead of print.

ABSTRACT

Homologous recombination is a key evolutionary force that varies considerably across bacterial species. However, how the landscape of homologous recombination varies across genes and within individual genomes has only been studied in a few species. Here, we used Approximate Bayesian Computation to estimate the recombination rate along the genomes of 145 bacterial species. Our results show that homologous recombination varies greatly along bacterial genomes and shapes many aspects of genome architecture and evolution. The genomic landscape of recombination presents several key signatures: rates are highest near the origin of replication in most species, patterns of recombination generally appear symmetrical in both replichores (i.e. replicational halves of circular chromosomes) and most species have genomic hotspots of recombination. Furthermore, many closely related species share conserved landscapes of recombination across orthologs indicating that recombination landscapes are conserved over significant evolutionary distances. We show evidence that recombination drives the evolution of GC-content through increasing the effectiveness of selection and not through biased gene conversion, thereby contributing to an ongoing debate. Finally, we demonstrate that the rate of recombination varies across gene function and that many hotspots of recombination are associated with adaptive and mobile regions often encoding genes involved in pathogenicity.

PMID:39718992 | DOI:10.1093/nar/gkae1265

J Clin Invest. 2024 Dec 24:e174249. doi: 10.1172/JCI174249. Online ahead of print.

ABSTRACT

KRAS is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with G12C mutation and advanced our understanding of its function. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V transgenic mouse model. We explore the therapeutic potential of KRASG12V degradation and characterize its impact on the tumor microenvironment (TME). Our study reveals that degrading KRASG12V abolishes lung and pancreatic tumors in mice and causes a robust inhibition of KRAS-regulated cancer intrinsic signaling. Importantly, targeted degradation of KRASG12V reprograms the TME towards a stimulatory milieu and drives antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides important insights into the impact of degrading KRASG12V on both tumor progression and immune response, highlighting degraders as a powerful strategy for targeting KRAS mutant cancers.

PMID:39718828 | DOI:10.1172/JCI174249

Mol Biol Cell. 2024 Dec 24:mbcE24060245. doi: 10.1091/mbc.E24-06-0245. Online ahead of print.

ABSTRACT

The question of how changes in chemoattractant concentration translate into the chemotactic response of immune cells serves as a paradigm for the quantitative understanding of how cells perceive and process temporal and spatial information. Here, using a microfluidic approach, we analyzed the migration of neutrophil-like HL-60 cells to a traveling wave of the chemoattractants fMLP and leukotriene B4 (LTB4). We found that under a pulsatile wave that travels at a speed of 95 and 170 µm/min, cells move forward in the front of the wave but slow down and randomly orient at the back due to temporal decrease in the attractant concentration. Under a slower wave, cells re-orient and migrate at the back of the wave; thus, cell displacement is canceled out or even becomes negative as cells chase the receding wave. FRET-based analysis indicated that these patterns of movement correlated well with spatiotemporal changes in Cdc42 activity. Furthermore, pharmacological perturbations showed that (re-)orientation in front and back of the wave had different susceptibility to Cdc42 and ROCK inhibition. These results suggest that pulsatile attractant waves may recruit or disperse neutrophils, depending on their speed and degree of cell polarization.

PMID:39718770 | DOI:10.1091/mbc.E24-06-0245

Plant Cell Environ. 2024 Dec 24. doi: 10.1111/pce.15347. Online ahead of print.

ABSTRACT

Lymantria xylina is the most important defoliator, damaging the effective coastal windbreak tree species Casuarina equisetifolia. However, the underlying genetic mechanisms through which C. equisetifolia responds to L. xylina attacks remain unknown. Here, we compared the transcriptional, phytohormone and metabolic differences between susceptible (S) and resistant (R) C. equisetifolia cultivars in response to L. xylina feeding. The main L. xylina-induced resistance in C. equisetifolia was a jasmonate (JA) response and JA synthesis was highly induced by L. xylina feeding at both the transcriptional and metabolic levels, thus promoting flavonoid accumulation. The JA response was highly activated by L. xylina feeding on the R but not in the S cultivar, although the JA signalling pathway was intact in both cultivars. We found a single amino acid mutation in the homologues of glutamate receptor-like protein 3.6 (CeGLR3.6T807I) in the S cultivar. Compared with the GLR3.6 homologues in the R cultivar, phosphorylation of CeGLR3.6T807I was not induced by insect feeding, leading to a decreased JA response in the S cultivar. Collectively, this study provides new insights into the function of CeGLR3.6 in regulating the JA response of C. equisetifolia to L. xylina feeding.

PMID:39718115 | DOI:10.1111/pce.15347

Biomed Khim. 2024 Dec;70(6):394-402. doi: 10.18097/PBMC20247006394.

ABSTRACT

Anuclear blood cells, platelets, are the basis for the formation of blood clots in human vessels. While antiplatelet therapy is most often used after ischemic events, there is a need for its personalization due to the limited effectiveness and risks of bleeding. Previously, we developed a series of computational models to describe intracellular platelet signaling and a set of experimental methods to characterize the platelets of a given patient. To build a personalized model of platelet signaling, we also conducted research on platelet proteomics. The aim of this study was to personalize the central module of intracellular platelet signaling responsible for the formation of calcium oscillations in response to activation. The model consists of 26 ordinary differential equations. To personalize the model, proteomics data were used and unknown model parameters were selected based on experimental data on the shape and frequency of calcium oscillations in single platelets. As a result of the study, it has been shown that the key personalized parameters of the platelet oscillatory response are the degree of asymmetry of a single calcium spike and the maximum frequency of oscillations. Based on the listed experimentally determined parameters and proteomics data, an algorithm for personalization of the model has been proposed. Here we considered three healthy pediatric donors of different ages. Based on the models, personal curves of platelet calcium response to activation were obtained. The analysis of the models has shown that while there is a large heterogeneity of individual indicators of intracellular signaling, such as the activity of calcium pumps (SERCA) and inositoltriphosphate (IP₃) receptors (IP₃R), these indicators compensate each other in each donors. This observation is confirmed by the analysis of proteomics data from 15 healthy patients: this analysis demonstrates a correlation between the total amount of SERCA and IP₃R. Thus, several new features of human platelet calcium signaling are shown and an algorithm for personalizing its model is proposed.

PMID:39718102 | DOI:10.18097/PBMC20247006394

Biomed Khim. 2024 Dec;70(6):381-393. doi: 10.18097/PBMC20247006381.

ABSTRACT

The review summarizes recent achievements and future prospects in the use of chronobiotics for regulating circadian rhythms regulation. Special attention is paid to the mechanisms' action, their classification, and the impact of chemical interventions on the biological clock. Chronobiotics defined as a diverse group of compounds capable of restoring disrupted circadian functions, addressing challenges such as irregular work schedules, artificial light exposure or ageing. The review categorizes these compounds by their pharmacological effects, molecular targets, and chemical structures, underlining their ability to enhance or inhibit key circadian components like CLOCK, BMAL1, PER, and CRY. A particular focus is placed on the therapeutic applications of chronobiotics, including their potential for treating sleep disorders, metabolic issues, and age-related rhythm disturbances, underscoring their wide-ranging applicability in health care. Chronobiotic compounds have promising roles in maintaining physiological rhythms, supporting healthy aging, and enhancing personalised health care. Given their diverse therapeutic potential, chronobiotics are positioned as a significant avenue for further clinical application, marking them as a crucial area of ongoing research and innovation.

PMID:39718101 | DOI:10.18097/PBMC20247006381

Elife. 2024 Dec 24;13:RP99833. doi: 10.7554/eLife.99833.

ABSTRACT

An unprecedented amount of SARS-CoV-2 data has been accumulated compared with previous infectious diseases, enabling insights into its evolutionary process and more thorough analyses. This study investigates SARS-CoV-2 features as it evolved to evaluate its infectivity. We examined viral sequences and identified the polarity of amino acids in the receptor binding motif (RBM) region. We detected an increased frequency of amino acid substitutions to lysine (K) and arginine (R) in variants of concern (VOCs). As the virus evolved to Omicron, commonly occurring mutations became fixed components of the new viral sequence. Furthermore, at specific positions of VOCs, only one type of amino acid substitution and a notable absence of mutations at D467 were detected. We found that the binding affinity of SARS-CoV-2 lineages to the ACE2 receptor was impacted by amino acid substitutions. Based on our discoveries, we developed APESS, an evaluation model evaluating infectivity from biochemical and mutational properties. In silico evaluation using real-world sequences and in vitro viral entry assays validated the accuracy of APESS and our discoveries. Using Machine Learning, we predicted mutations that had the potential to become more prominent. We created AIVE, a web-based system, accessible at https://ai-ve.org to provide infectivity measurements of mutations entered by users. Ultimately, we established a clear link between specific viral properties and increased infectivity, enhancing our understanding of SARS-CoV-2 and enabling more accurate predictions of the virus.

PMID:39717902 | DOI:10.7554/eLife.99833

Brain Behav Immun Health. 2024 Nov 28;43:100918. doi: 10.1016/j.bbih.2024.100918. eCollection 2025 Feb.

ABSTRACT

Prebiotic dietary fiber (PDF) may reduce feelings of stress or improve mood in healthy individuals. Yet gut intervention studies that focus on mood in daily life are lacking and few studies include extensive biological sample analyses to gain mechanistic insights. As part of a larger randomized placebo-controlled crossover study including healthy individuals, we explored the effects of 12 weeks of PDF (acacia gum and carrot powder) on everyday mood, as measured with ecological momentary assessment (EMA). Microbiome composition and levels of microbial metabolites, endocrine, and inflammatory markers were determined prior to and after both intervention phases. Fifty-four participants completed the study. The intervention significantly increased daily positive affect (PA) and reduced daily negative affect (NA) in female but not male participants. The intervention-induced reduction in NA was associated with an increase in microbial diversity in female participants. The intervention did not significantly affect levels of fecal short chain fatty acids, cortisol, and inflammatory markers. This is one of the first studies to show that a dietary fiber intervention can positively alter mood as it is experienced in everyday life. Overall, our findings may stimulate more targeted gut-microbiome interventions and detection of its mental health effects in real life.

PMID:39717875 | PMC:PMC11665422 | DOI:10.1016/j.bbih.2024.100918

Microlife. 2024 Dec 23;5:uqae025. doi: 10.1093/femsml/uqae025. eCollection 2024.

ABSTRACT

Evolutionary processes acting on populations of organized molecules preceded the origin of living organisms. These prebiotic entities were independently and repeatedly produced [i.e. (re)-produced] by the assembly of their components, following an iterative process giving rise to nearly but not fully identical replicas, allowing for a prebiotic form of Darwinian evolution. Natural selection favored the more persistent assemblies, some possibly modifying their own internal structure, or even their environment, thereby acquiring function. We refer to these assemblies as proto-organs. In association with other assemblies (e.g. in a coacervate or encapsulated within a vesicle), such proto-organs could evolve and acquire a role within the collective when their coexistence favored the selection of the ensemble. Along millions of years, an extraordinarily small number of successful combinations of those proto-organs co-occurring in spatially individualizing compartments might have co-evolved forming a proto-metabolic and proto-genetic informative network, eventually leading to the selfreplication of a very few. Thus, interactions between encapsulated proto-organs would have had a much higher probability of evolving into proto-organisms than interactions among simpler molecules. Multimolecular forms evolve functions; thus, functional organs would have preceded organisms.

PMID:39717754 | PMC:PMC11664216 | DOI:10.1093/femsml/uqae025

Onco Targets Ther. 2024 Dec 18;17:1197-1207. doi: 10.2147/OTT.S492659. eCollection 2024.

ABSTRACT

INTRODUCTION: The FGFR3-TACC3 fusion gene exists in a variety of malignant tumors, including bladder cancer. In our ongoing research on the CRISPR-Cas13a gene-editing system, we reported the use of CRISPR-Cas13a gene-editing system to knockout FGFR3-TACC3 and inhibit the proliferation of bladder tumor cells.

PURPOSE: This study aimed to use the CRISPR-Cas13a gene-editing system to target the FGFR3-TACC3 fusion gene in bladder cancer cells, which has the potential to be a new and effective treatment for bladder cancer.

MATERIALS AND METHODS: The efficacy of the CRISPR-Cas13a gene-editing system was analysed by qRT-PCR. The inhibitory effects of Cas13a-mediated knockdown of the FGFR3-TACC3 fusion gene on the proliferation of RT4 and RT112 cell lines were assessed utilizing CCK-8, EdU, and organoid formation assays. Subsequently, the comparative tumorigenic capability of RT4 cells with FGFR3-TACC3 knockdown achieved by Cas13a was examined in a nude mouse model.

RESULTS: At the cellular level, the comparative analysis of FGFR3-TACC3 knockdown efficacy between CRISPR-Cas13a and shRNA revealed a more pronounced reduction with the former. This knockdown effectively curtailed cellular proliferation, with CRISPR-Cas13a-mediated knockdown exhibiting a superior inhibitory effect over shRNA-mediated knockdown. In organoid cultures derived from RT4 cells, a similar trend was observed, with Cas13a-mediated knockdown of FGFR3-TACC3 leading to a more substantial suppression of proliferation compared to shRNA-mediated knockdown. In vivo tumor models corroborated these findings, demonstrating a significantly diminished tumor volume in the Cas13a-treated cohort relative to both the control and shRNA-treated groups.

CONCLUSION: The CRISPR-Cas13a gene-editing system has been demonstrated to significantly suppress tumor proliferation both in vitro and in vivo, thereby presenting itself as a promising candidate for a novel and efficacious therapeutic intervention in bladder cancer treatment.

PMID:39717713 | PMC:PMC11664097 | DOI:10.2147/OTT.S492659

Ecol Evol. 2024 Dec 22;14(12):e70760. doi: 10.1002/ece3.70760. eCollection 2024 Dec.

ABSTRACT

Long-term studies depicting the multicontinental invasion trajectories of species are often constrained by the scarcity of documented records, especially for invertebrates. The red swamp crayfish, Procambarus clarkii (Decapoda: Cambaridae), stands out as an uncommon example of hypersuccessful invasive species with a well-known invasion history at both regional and global levels. This allows for the use of its records to track distribution dynamics and bioclimatic preferences over time. Through multiple temporal comparisons, the global bioclimatic tendencies of the species have been explored over a period exceeding a century (1854-2023) using linear models with generalized least squares estimation and two-sample t-tests. This specific setup provides a rare focus on biological invasions at both broad temporal and spatial scales. The results highlight climatic trends in the invasion process of the species, including decreases in the values of bioclimatic variables associated with temperature and precipitation. This trend encompasses not only mean values but also both extreme (minimum and maximum) and is coupled with increases in elevation and aridity values in the areas with the presence of the species. The findings indicate that the species can engage in new ecological interactions and further affect range-restricted species in climatic refuges once considered protected. These findings help anticipate changes in the species' invasion trajectory, suggesting possible expansions into colder, less humid climates and higher altitudes. This knowledge supports effective monitoring and early detection for management and conservation efforts.

PMID:39717651 | PMC:PMC11663627 | DOI:10.1002/ece3.70760

Adv Sci (Weinh). 2024 Dec 23:e2404620. doi: 10.1002/advs.202404620. Online ahead of print.

ABSTRACT

Cell signaling pathways are enriched for biological processes crucial for cellular communication, response to external stimuli, and metabolism. Here, a cell signaling-focused CRISPR screen identified cytochrome c oxidase subunit 4 isoform 1 (COX4I1) as a novel vulnerability in acute myeloid leukemia (AML). Depletion of COX4I1 hindered leukemia cell proliferation and impacted in vivo AML progression. Mechanistically, loss of COX4I1 induced mitochondrial stress and ferroptosis, disrupting mitochondrial ultrastructure and oxidative phosphorylation. CRISPR gene tiling scans, coupled with mitochondrial proteomics, dissected critical regions within COX4I1 essential for leukemia cell survival, providing detailed insights into the mitochondrial Complex IV assembly network. Furthermore, COX4I1 depletion or pharmacological inhibition of Complex IV (using chlorpromazine) synergized with venetoclax, providing a promising avenue for improved leukemia therapy. This study highlights COX4I1, a nuclear encoded mitochondrial protein, as a critical mitochondrial checkpoint, offering insights into its functional significance and potential clinical implications in AML.

PMID:39716856 | DOI:10.1002/advs.202404620

Acta Paediatr. 2024 Dec 23. doi: 10.1111/apa.17553. Online ahead of print.

ABSTRACT

BACKGROUND: The Special Issue articles describe six systems of parental interventions and developmental care several differences among each of the approaches. Nevertheless, on a deeper level there are profound similarities shared across the six systems. These similarities are at the heart of developmental care in general and parental interventions in particular.

AIM: The aim of this paper is to highlight the commonalities of these systems of developmental processes and parental interventions.

MATERIALS AND METHODS: We discuss the concept of symbiosis as a theoretical framework for entering into a new understanding of mother-infant and family systems biology based on perspectives that share themes of interconnection and mutualism.

RESULTS: There are many rigorous, empirical studies of co-regulation, mutualism and interdependence in the human parent-offspring system that is moving us forward into this new territory. Perspectives that emphasize interconnection and interpenetration, reciprocity and mutualism, and integration over reduction are expanding to fill the spaces needed to answer today's questions.

DISCUSSION: Recent contributions of perspectives on neurocognitive development have buttressed the symbiosis view with constructs of prenatal origins, such as 'co-embodiment' and 'co-homeostasis', that illuminate maternal-fetal reciprocities seen to underlie initiation and maintenance of developmental trajectories essential to support fetuses born prematurely into a NICU environment.

CONCLUSION: The six systems of parental intervention and developmental care presented in this Special Issue represent foundational approaches to developmental care for prematurely born infants. All these approaches recognize forms of reciprocity and mutualism on many levels, always including the infants as active parts of multiple regulatory systems.

PMID:39716839 | DOI:10.1111/apa.17553

J Integr Bioinform. 2024 Dec 25. doi: 10.1515/jib-2022-0036. Online ahead of print.

ABSTRACT

Breast cancer has the highest incidence and is the fifth cause of death in cancers. Progression is one of the important features of breast cancer which makes it a life-threatening cancer. MicroRNAs are small RNA molecules that have pivotal roles in the regulation of gene expression and they control different properties in breast cancer such as progression. Recently, systems biology offers novel approaches to study complicated biological systems like miRNAs to find their regulatory roles. One of these approaches is analysis of weighted co-expression network in which genes with similar expression patterns are considered as a single module. Because the genes in one module have similar expression, it is rational to think the same regulatory elements such as miRNAs control their expression. Herein, we use WGCNA to find important modules related to breast cancer progression and use hypergeometric test to perform miRNA target enrichment analysis and find important miRNAs. Also, we use negative correlation between miRNA expression and modules as the second filter to ensure choosing the right candidate miRNAs regarding to important modules. We found hsa-mir-23b, hsa-let-7b and hsa-mir-30a are important miRNAs in breast cancer and also investigated their roles in breast cancer progression.

PMID:39716374 | DOI:10.1515/jib-2022-0036

BioData Min. 2024 Dec 24;17(1):60. doi: 10.1186/s13040-024-00416-7.

ABSTRACT

Pathway analysis is a powerful approach for elucidating insights from gene expression data and associating such changes with cellular phenotypes. The overarching objective of pathway research is to identify critical molecular drivers within a cellular context and uncover novel signaling networks from groups of relevant biomolecules. In this work, we present PathSingle, a Python-based pathway analysis tool tailored for single-cell data analysis. PathSingle employs a unique graph-based algorithm to enable the classification of diverse cellular states, such as T cell subtypes. Designed to be open-source, extensible, and computationally efficient, PathSingle is available at https://github.com/zurkin1/PathSingle under the MIT license. This tool provides researchers with a versatile framework for uncovering biologically meaningful insights from high-dimensional single-cell transcriptomics data, facilitating a deeper understanding of cellular regulation and function.

PMID:39716187 | DOI:10.1186/s13040-024-00416-7

ArXiv [Preprint]. 2024 Dec 13:arXiv:2412.10262v1.

ABSTRACT

Computational variant effect predictors (VEPs) are providing increasingly strong evidence to classify the pathogenicity of missense variants. Precision vs. recall analysis is useful in evaluating VEP performance, especially when adjusted for imbalanced test sets. Here, we describe VEPerform, a web-based tool for evaluating the performance of VEPs at the gene level using balanced precision vs. recall curve (BPRC) analysis.

PMID:39713801 | PMC:PMC11661297

Methods Mol Biol. 2025;2884:369-387. doi: 10.1007/978-1-0716-4298-6_22.

ABSTRACT

Amyloidosis diseases are characterized by protein misfolding, which forms insoluble beta-sheet fibrils progressively deposited in tissues. Deposition in the form of amyloid aggregates can occur in various organs, damaging their structure and function. The hallmark of amyloidosis is aberrant interactions leading to protein aggregation and proteotoxicity. Accordingly, amyloidosis-related samples represent a valuable source of information to generate new knowledge useful for diagnostic, prognostic, and therapeutic purposes. In this scenario, we outline the path to apply computational methods and strategies based on the combination of proteomics and systems biology approaches. In addition to algorithms useful for subtyping amyloid deposits or assessing proteome recovery after drug treatment, our chapter provides workflows based on protein-protein interaction and protein co-expression network models. In particular, the main steps to reconstruct and analyze them at both functional and topological levels are described. Our chapter aims to provide tools and instructions to identify and monitor prognostic, diagnostic, and therapeutic markers and to shed light on the processes, pathways, and functions affected by amyloidogenic proteins.

PMID:39716014 | DOI:10.1007/978-1-0716-4298-6_22

Nature. 2024 Dec 23. doi: 10.1038/s41586-024-08555-x. Online ahead of print.

NO ABSTRACT

PMID:39715925 | DOI:10.1038/s41586-024-08555-x

Genome Res. 2024 Dec 23:gr.279864.124. doi: 10.1101/gr.279864.124. Online ahead of print.

ABSTRACT

While the production of a draft genome has become more accessible due to long-read sequencing, the annotation of these new genomes has not been developed at the same pace. Long-read RNA sequencing (lrRNA-seq) offers a promising solution for enhancing gene annotation. In this study, we explore how sequencing platforms, Oxford Nanopore R9.4.1 chemistry or PacBio Sequel II CCS, and data processing methods influence evidence-driven genome annotation using long reads. Incorporating PacBio transcripts into our annotation pipeline significantly outperformed traditional methods, such as ab initio predictions and short-read-based annotations. We applied this strategy to a nonmodel species, the Florida manatee, and compared our results to existing short-read-based annotation. At the loci level, both annotations were highly concordant, with 90% agreement. However, at the transcript level, the agreement was only 35%. We identified 4,906 novel loci, represented by 5,707 isoforms, with 64% of these isoforms matching known sequences in other mammalian species. Overall, our findings underscore the importance of using high-quality curated transcript models in combination with ab initio methods for effective genome annotation.

PMID:39715684 | DOI:10.1101/gr.279864.124